Abstract
B‐cell non‐Hodgkin's lymphoma (NHL) is a class of heterogeneous diseases with variable clinical outcomes. Immunosuppression is particularly common in the subtypes of lymphoma with poor prognosis, but the underlying mechanism remains unclear. Using a RT‐PCR array analysis, we have identified that glycosyltransferase 1 domain‐containing 1 (GLT1D1), an enzyme that transfers glycosyl groups to proteins, is highly upregulated in the incurable subtype of B‐cell NHL and in early relapse diffuse large B‐cell lymphoma. Analysis of clinical specimens revealed that GLT1D1 expression was positively correlated with the level of glycosylated programmed cell death‐ligand 1 (PD‐L1) in B‐cell NHL and that high GLT1D1 expression was associated with poor prognosis. Mechanistically, we showed that GLT1D1 transferred N‐linked glycans to PD‐L1, thus promoting the immunosuppressive function of glycosylated PD‐L1. Downregulation of GLT1D1 resulted in a decrease of glycosylated PD‐L1 and enhanced cytotoxic T‐cell function against lymphoma cells. In vivo, overexpression of GLT1D1 promoted tumor growth by facilitating tumor immune escape through increased levels of PD‐L1. Our work has identified GLT1D1 as a predictive biomarker for B‐cell NHL. It has also shown that this enzyme enhances PD‐L1 stabilization via N‐glycosylation, thus promoting immunosuppression and tumor growth. As such, GLT1D1 might be a novel therapeutic target for the treatment of B‐NHL.
Highlights
Non-Hodgkin’s lymphoma (NHL) is a cancer originated in the lymphatic system, characterized by the neoplastic transformation and abnormal proliferation of lymphocytes
As high level of programmed cell death-ligand 1 (PD-L1) is associated with poor clinical outcome in diffuse large B-cell lymphoma (DLBCL) (Chen et al, 2013; Georgiou et al, 2016; Kiyasu et al, 2015), and N-glycosylated PD-L1 has been shown to be essential for PD-L1 stabilization and function (Hsu et al, 2018; Li et al, 2016, 2018), a quantitative real-time polymerase chain reaction array containing 50 key genes encoding enzymes that post-translationally add or remove sugar residues to or from proteoglycans and glycoproteins (Table S1) was used to investigate whether N-glycosyltransferase changes are involved in regulation of PD-L1 in B-cell non-Hodgkin’s lymphoma (NHL)
The results revealed that among the genes that were differentially expressed between the highly curable B-NHLs (DLBCL and Burkitt lymphoma (BL)) and the incurable mantle cell lymphoma (MCL) cells, glycosyltransferase 1 domain-containing protein 1 (GLT1D1) was highly expressed in the MCL, which has the worst prognosis among the 3 subtypes of B-cell NHLs (Fig. 1A)
Summary
Non-Hodgkin’s lymphoma (NHL) is a cancer originated in the lymphatic system, characterized by the neoplastic transformation and abnormal proliferation of lymphocytes. NHL is among the ten most commonly diagnosed cancers both in Western countries and in Asia. NHLs are a heterogeneous group of neoplasms mostly arise from B cells. Subtypes of NHLs that involve B cells include diffuse. Abbreviations ASCT, autologous stem cell transplantation; BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; GEO, Gene Expression Omnibus; GLT1D1, glycosyltransferase 1 domain-containing 1; HL, Hodgkin lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TM, tunicamycin.
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